The invention relates to a new dried implant composition for preparing a new injectable aqueous implant formulation for use in tissue regeneration, notably oral tissue regeneration, in particular in regeneration of alveolar bone, root cementum or the periodontal ligament (PDL), that is apt to be injected into periodontal pockets through a tapering system and a gauge 18 cannula, as well as the new injectable aqueous implant formulation prepared using that dried implant composition, a process and a kit for preparing that new injectable aqueous implant formulation.
There are a number of risk factors for periodontal disease such as poor oral hygiene, tobacco smoking, diabetes, obesity, genetic disposition, age and socio-economic status that facilitate bacterial accumulation, biofilm formation and infection of the gingival sulcus and hence the formation of a gingival inflammation or gingivitis. If left untreated, the inflammation progresses along the tooth root and causes destruction of the PDL and the surrounding alveolar bone, which is then referred to periodontitis. As periodontal disease progresses, pockets develop between tooth and the soft tissue and continue to grow until the tooth loses its stability and may fall off. Clinical signs of periodontal disease are inflammation of soft tissues, bleeding on (tissue-) probing, possibly accompanied with suppuration, and radiographic loss of alveolar bone. A dentist can determine the presence and extent of periodontal disease using a probe to measure the depth of periodontal pockets, i.e. the depth between soft tissue or bone and the tooth, which is referred to the loss of clinical (tooth) attachment.
Guided Tissue Regeneration (GTR) is a widely used surgical procedure to treat the loss of periodontal structures. In this procedure, the periodontist obtains access to the diseased root and surrounding bone by incisions of the soft tissues to raise a flap. The next step is debridement of the diseased bone, soft tissues and the root surface by suitable hand instruments, ultrasonic or laser devices where diseased tissues are removed and the root surface is scaled and planed. After debridement larger bone defects are filled with a bone regeneration material. Guided tissue regeneration barriers such as Geistlich Bio-Gide®, described in EP-B1-1676592 and commercially available from Geistlich Pharma AG, are placed over the bone regeneration material in deeper osseous defects. The periodontist closes the flap by appropriate sutures. Then, the gingiva, epithelial attachment, bone and periodontal attachment between the bone and tooth reform. While this procedure has been effective, incisions in the gingiva cause patient discomfort, pain, swelling, gingival recession, sensitive teeth, a long healing time and increase the possibility of re-infection.
Numerous natural and synthetic materials and compositions have been used as bone regeneration materials at the site of a bone defect.
A well-known natural, osteoconductive bone substitute material that promotes bone growth in periodontal osseous defects is Geistlich Bio-Oss®, commercially available from Geistlich Pharma AG. That material is manufactured from natural bone by a process described in U.S. Pat. Nos. 5,167,961 and 5,417,975, which enables preservation of the trabecular architecture and nanocrystalline structure of the natural bone, resulting in an excellent osteoconductive matrix which is not or very slowly resorbed.
To reduce the above-mentioned drawbacks related to incisions in the gingiva, there is a need for an injectable implant formulation.
For easy acceptance by patients when injected into periodontal pockets and convenient manual injection using a syringe, that injectable aqueous implant formulation should be extrudable through a cannula not larger in diameter than a gauge 18 (0.838 mm inner diameter) cannula or needle, preferably with a force not exceeding 60 N.
For optimal oral tissue regeneration, in particular for regeneration of alveolar bone, root cementum or the periodontal ligament, it is desirable that the injected implant formulation provides a matrix of hydroxyapatite and collagen close to the natural in vivo environment in which such regeneration takes place.
Hydroxyapatite derived from natural bone is closer to the natural in vivo environment in which regeneration takes place than synthetic (non-biological) hydroxyapatite or ceramic.
Particles that are obtained by grinding hydroxyapatite derived from natural bone have a more irregular and longitudinal shape than the rounded particles obtained by grinding synthetic hydroxyapatite or ceramic: They thus present a higher risk of clogging a gauge 18 cannula. See FIG. 5 which represents on the left-hand-side a scanning electron micrograph (SEM) of nanocrystalline hydroxyapatite particles derived from natural bone and on the right-hand-side a SEM of synthetic beta-TCP particles. Results of extrusion through cannulae of formulations containing synthetic hydroxyapatite or ceramic particles are thus only partly predictive of extrusion of similar formulations containing hydroxyapatite particles derived from natural bone.
One important feature of human natural bone is the morphology and the very small size (nano-size) of the hydroxyapatite crystals, which for human bone mineral is: hexagonal space group P63/m, about 30 to 50 nm in length (c axis: [0,0,1]) and 14 to 25 nm in length (a and b axes: [1,0,0] and [0,1,0]). See Weiner, S. et al., 1992, FASEB, 6:879-885. To be closer to the natural environment in which regeneration takes place it is thus desirable to use nanocrystalline hydroxyapatite particles derived from natural bone, preferably with a morphology and size of crystals close to those of human natural bone.
U.S. 2012/0107401 describes flowable implantable osteoconductive matrices that comprise a mixture of 0.1-2 mm mineral particles of either ceramic such as synthetic hydroxyapatite and beta-TCP or hydroxyapatite derived from natural bone, collagen that can be soluble collagen or insoluble collagen derived from a human or animal source, and a therapeutic agent including a statin. Those flowable implantable osteoconductive matrices are taught to be suitable as putties or as gels that can be injected, sprayed or instilled to the target tissue site. The w/w ratio of ceramic to collagen is taught to be 0.15 to 22.5 (claims 4) or 1.5 to 11.5 (claim 5), the only specific ratios of ceramic to collagen disclosed being 5 and 4.83 (claims 2 and [0089], [0090]).
U.S. Pat. No. 7,322,825 discloses a method of treating periodontal disease by injection into periodontal pockets of a composition which is a mixture of finely ground bone particles of microcrystalline hydroxyapatite having a size of 50 to 400 μm and “free collagen” particles of less than 1 mm in diameter, those “free collagen” particles being taught to be non-crosslinked collagen small fibrils or gel containing fibrillar collagen and optionally a physiologically compatible thickener. That mixture only has a low enough viscosity to pass through an 18 gauge (0.838 mm inner diameter) needle, after an additional energy infusion by application of heat, e.g. through microwave radiation. According to that patent, crosslinked collagen such as Avitene or Collastat cannot be cut in pieces small enough to go through an 18-gauge needle. For specifically described compositions, the w/w ratio of hydroxyapatite to collagen is 0.5 to 1.5.
The method of treating periodontal disease of U.S. Pat. No. 7,322,825 has not met wide-spread use. Non-crosslinked collagen such as “free collagen” is far from a natural in vivo environment that is desirable for oral tissue regeneration, in particular for regeneration of alveolar bone, root cementum or the periodontal ligament.
U.S. Pat. No. 5,352,715 discloses an injectable ceramic formulation for soft and hard tissue repair and augmentation which comprises collagen and calcium phosphate ceramic particles in a pharmaceutically acceptable fluid carrier, wherein the calcium phosphate ceramic particles have a size of 50 to 250 μm and the w/w ratio of the phosphate ceramic particles to collagen is from 1/19 to 1/1, preferably from 1/4 to 1/2. According the teaching of that patent, calcium phosphate ceramic particles are preferably sintered ceramic particles of non-biological (synthetic) origin and the collagen is substantially free from crosslinking, i.e. deprived of telopeptides, the preferred collagen being a purified atelopeptide reconstituted collagen. That injectable ceramic formulation can pass through a 20 gauge (0.603 mm inner diameter) needle.
A combination of telopeptide deprived collagen and synthetic calcium phosphate particles is far from the natural in vivo environment in which regeneration takes place.
EP-0270254-A2 discloses a dried implant composition comprising a mixture containing, by weight exclusive of moisture, 2-40% of reconstituted fibrillary atelopeptide collagen which is substantially free from crosslinking and 60-98% of a tricalcium phosphate such as hydroxyapatite with a size range 100-2000 μm, the mass ratio of tricalcium phosphate to atelopeptide collagen being thus from 1.5 to 49. That dried implant composition is treated with gamma radiation to improve both biological and handling properties.
A combination of collagen deprived of telopeptides and synthetic tricalcium phosphate particles is far from the natural in vivo environment in which regeneration takes place.
An injectable aqueous implant formulation containing collagen cannot be sterilized by gamma- or X-ray-irradiation. Stability over a long period (more than 6 months) of a sterile injectable aqueous implant composition would require drastic aseptic conditions of preparation and storage which are not always readily available: It is therefore desirable to provide a dried implant composition which is stable over a long period and apt to give by rehydration an injectable aqueous implant formulation.